Download Management of…… Chronic Liver Disease

Management of……
Chronic Liver
Disease
Dr Melissa Haines
Gastroenterologist
Waikato Hospital
Outline

Recognising and diagnosing the patient with
chronic liver disease

Causes of chronic liver disease in NZ



Investigations
Management
Complications of end-stage liver disease

Management
John

54 year old man

Recently moved to NZ from Australia

PMHx




Type 2 diabetes mellitus 3 yrs
Diet-controlled
No complications
No medications
John

FHx:


No liver disease, viral hepatitis, HCC
SHx:




Lives with parents
Unemployed
Smoker 30 pk years
Alcohol
• 20+ years heavy alcohol intake
• Cask wine per day
• 1L bottle of spirits per week

Previous IVDU in Australia
• Last injected 10 years ago
John

Examination




Palmer erythema, jaundice, muscle wasting,
spider naevi, gynaecomastia
Dupeytren’s contracture
BMI 20
Abdomen
•
•
•
•
•

Soft
Tender RUQ
Hepatomegaly 19cm
Splenomegaly
No shifting dullness
No pedal oedema
Chronic Liver Disease
Laboratory Investigations

Which blood tests are most useful in
determining severity of CLD?
ALT
 Platelets
 Albumin
 Bilirubin
 Sodium
 INR

Laboratory Investigations

Which blood tests are most useful in
determining severity of CLD?






ALT
Platelets  Hepatic fibrosis and portal HT
Albumin  Hepatic synthetic dysfunction
Bilirubin  Destruction of liver parenchyma
and bile ducts
Sodium
INR  Hepatic synthetic dysfunction or
vitamin K malabsorption
John’s results

Hb 107 (macrocytic), plts 120, WCC 8.5

Cre 0.1, urea 5.7, Na 128, K 3.5

INR 1.2, alb 25

Bili 90, ALT 28, AST 87, GGT 396, ALP 322
John
What are the possible causes
of his chronic liver disease?
Causes of CLD
Alcohol
 Hepatitis B
 Hepatitis C
 Non-alcoholic steatosis (NASH)
 Autoimmune liver disease
 Genetic or metabolic
 Drugs or toxins

Causes of Chronic Liver Disease
ALCOHOL
End-Stage Liver Disease in USA
Liver-Related Mortality
25,000 deaths per annum
other
15%
HBV
5%
Alcohol
50%
HCV
30%
Alcoholic Liver Disease

Recent and past alcohol consumption should be
assessed in all cases of liver disease

Most useful lab marker is GGT

Fatty liver, hepatitis and cirrhosis

20g/day woman, 40g/day man

HCV + alcohol = more severe liver disease

Abstinence from alcohol is the major factor which
influences survival
Alcohol Abstinence
Brief intervention
 Referral to drug and alcohol service
 Helpline
 Counselling
 Pharmacotherapy

Acamprosate
 Naltrexone
 Disulfiram


Residential rehabilitation
Brief intervention: FLAGS
Feedback
The nature and extent of alcoholrelated problems
Listen
Advise
To patient concerns
Goals
Negotiate clinically appropriate goals
acceptable to the patient
Strategies
Specific suggestions to modify drinking
Patient clearly to reduce
consumption
Alcoholic Liver Disease

Thiamine


100mg IM/IV then orally daily until
sustained abstinence
Oral diazepam/oxazepam for
withdrawal

? Inpatient
Causes of Chronic Liver Disease
Hepatitis B
End-Stage Liver Disease in New
Zealand
Liver-Related Mortality
USA
25,000 deaths per annum
New Zealand
300 deaths per annum
other
15%
HBV
5%
Alcohol
40%
other
5%
Alcohol
50%
HCV
30%
HCV
5%
HBV
50%
1.
2m
illi
on
Asian,
Pacific 395,000
295000
Maori,
625000
Asia-Pacific
European
2.7million
Estimated 90,000 HBsAg+
living in New Zealand in 2006
http://www.stats.govt.nz/products-and-services/Articles/pop-proj-Jun04.htm
Transmission of Hepatitis B Infection
Transfusion and
transplant recipients
Sexual partners
of known chronic
carrier
Healthcare
workers
Newborns of long-term
carriers
Intravenous
drug users
Prisoners and other
institutionalised people
They are all healthy
carriers!
Chronic hepatitis B has serious
long-term consequences
HBsAg-positive
Chronic Hepatitis B
30%
Cirrhosis
Liver Failure
Hepatocellular
carcinoma (HCC)
Death
Lok et al 2002
Natural History of Chronic
HBV Infection
HBsAg
Anti-HBs
Serology
HBeAg
Anti-HBe
ALT
level
HBV DNA
level
(viremia)
Disease
Chronicity
Stage
0
Minimal
inflammation
Chronic active
hepatitis
Cirrhosis/HCC
Normal to
cirrhosis/HCC
Immune tolerant
(phase I)
Immune Active
(phase II)
Non-Replicative
(phase III)
Resolved
10
20
30
40
Years
50
60
70
John

Which HBV tests would you order to
screen for HBV
HBeAg
 HBsAB
 HBV DNA
 HBsAg
 HBcAB

John

Which HBV tests would you order to
screen for HBV
HBeAg
 HBsAB
 HBV DNA
 HBsAg
 HBcAB

Is HBV Serology Confusing??
HBV Serology
sAg determines carrier status / chronic
infection
 eAg determines replication and infectivity

cAb confirms natural infection
 sAb confirms immunity


HBV DNA (viral load) measures infectivity
and replication
Indications for Treatment of
Chronic HBV

Patients with active liver disease:



Abnormal liver function tests (AST, ALT)
HBeAg positive and > 105 HBV DNA
HBeAg negative and > 104 HBV DNA
• Treat if active hepatitis (biochemical or histologic)
Lok AS, et al. Hepatology. 2001;34:1225-1241.
Current approaches to treatment of
chronic hepatitis B
Drug types

Anti-viral agents



Lamivudine
Adefovir dipivoxil*
Immunomodulators

Interferon-
Treatment duration

Continuous long term

Finite course

Undefined: dependant
on response
Hepatitis B can be prevented!
If you have never had hepatitis B,
you can get 3 shots . . .
1
2
3
. . . and get long lasting protection.
Causes of Chronic Liver Disease
Hepatitis C
HCV Infection




30,000 New Zealanders have HCV infection
Most are young, ex-IVDU
9% are cirrhotic at presentation
 referrals to Hepatitis Clinics
 detection
• awareness of risk factors
  demand for treatment
• more effective therapies


HBV still main cause of end-stage liver disease in
NZ BUT  HCV-ESLD over next decade
Risk factors for HCV exposure
Tattoo Other
1%
2%
HCV+ partner
2%
None
8%
Blood
products
13%
Intravenous
drug use
74%
Natural History of Hepatitis C
Acute HCV infection
70-80% chronic HCV
Chronic hepatitis:
Minimal-severe
inflammation & fibrosis
Cirrhosis develops in
10-15% over 20-30yrs
Liver Failure
20-30% spontaneous clearance
Bridging fibrosis
Hepatocellular
carcinoma
Liver
transplantation
Death
Management of HCV

Diagnosis



Determine genotype



HCV IgG antibody positive
HCV RNA positive
1 & 4 ‘hard to treat’: 12 months, 55% cure
rate
2 & 3 ‘easy to treat’: 6 months, 80% cure rate
Treatment

Pegylated interferon + ribavirin
Causes of Chronic Liver Disease
NASH
Definition

Liver biopsy




Negligible alcohol
consumption


Macrovesicular
fatty change
Inflammation
With or without
fibrosis or
cirrhosis
<40g/wk
Absence HBV or
HCV
Epidemiology

Worldwide prevalence not determined

Most common liver disease in the
Western world and increasing

Affects all racial and ethnic groups


No age or sex predilection
Aetiology of NASH unknown
Association with Metabolic
Syndrome
Pathophysiology
Clinical Course
Treatment

No proven effective treatment for NASH

Modification of risk factors recommended




Weight loss and increased physical activity lead to
improvement in:





Obesity
Hyperlipidaemia
Poor diabetic control
Liver enzymes
Histology
Serum insulin levels
Quality of life (Hickman 2004, Dixon 2004, Peterson 2005)
Several potential treatments not routinely used in clinical
practice
Causes of Chronic Liver Disease
Autoimmune Liver Disease
Autoimmune Liver Disease

Autoimmune hepatitis






Primary biliary cirrhosis



Globulins (IgG)
Anti-nuclear antibody (ANA)
± Anti-smooth muscle antibody (SMA)
± Antibodies to liver-kidney microsome type 1 (antiLKM-1)
Rx: steroids, azathioprine
Anti-mitochondrial AB positive
Rx: ursodeoxycholic acid
Primary sclerosing cholangitis
Causes of Chronic Liver Disease
Genetic/Metabolic Disease
Genetic/Metabolic Disease

Genetic
haemochromatosis

Alpha1 antitrypsin
deficiency

Wilson’s disease
Haemochromatosis

HFE gene positive: autosomal recessive



Clinical





Asymptomatic
Arthralgias
Chronic liver disease
Elevated transferrin sats and ferritin


C282Y homozygous
C282Y/H63D compound heterozygote
Note: raised in inflammation, chronic liver disease
Rx: phlebotomy, avoid alcohol
Screen relatives
John’s results

HBsAg neg, HBsAB neg, HCV neg

Fe studies normal

Autoimmune screen negative
What would you do ?
Refer to gastroenterology unit
 Arrange screening for HCC

USS
 Tumour marker

• ? CEA
• ? CA19-9
• ? AFP

Vaccinate against HBV
What would you do?
Refer to gastroenterology unit Yes
 Arrange screening for HCC Yes


Which tumour marker
• CEA
• CA19-9
• AFP


USS
Vaccinate against HBV Yes
John






Diazepam for withdrawal
Parenteral thiamine initially (100mg IM),
then oral until sustained abstinence
IV vitamin K 10mg then orally for 3-5 days
Vaccinate against HBV
Referred to gastroenterology service
……….meanwhile John presents with leg
oedema, increased abdominal girth, shifting
dullness, Na 124
Portal Hypertension

Most common and life-threatening complications of CLD

Responsible for the most common complications:

Variceal bleeding

Ascites

Peripheral oedema

Hepatorenal syndrome (HRS)

Dilutional hyponatraemia

Encephalopathy
Ascites in Liver Cirrhosis
Differential diagnosis:









Cirrhosis
Hepatoma
TB
Peritoneal carcinomatosis
Right heart failure
Constrictive pericarditis
Nephrotic syndrome
Pancreatitis
Malignant chylous ascites
Pathophysiology of Ascites in Cirrhosis
Portal hypertension
Splanchnic arterial
vasodilation
Arterial hypotension
Activation of RAAS and SNS
vasoconstrictor systems
Vasoconstriction in renal
and other non-splanchnic
circulations
Sodium and water
retention
Ascites
Hepatorenal syndrome
 plasma renin
 noradrenaline
 aldosterone
 vasopressin
Impaired free water
excretion
Dilutional
hyponatraemia
Cirrhotic Ascites
Patient evaluation

Evaluate renal and
circulatory function

Serum urea, creatinine and
electrolytes

Ur protein (24 hr urine)

Ur Na+ (24 hr urine)

Arterial BP
Gines et al, NEJM,2004

Ascitic fluid analysis

Cell count

Bacterial culture

Total protein

Albumin

Cytology

Other tests as needed
John’s results




Serum creatinine 0.1
Serum albumin 24
Negative urinary
protein
Ascites



Albumin 3
Polymorph count 200
Cytology pending
What is the aetiology of John’s
ascites?
o Malignancy
o Infection
o Portal Hypertension
Ascitic Fluid Analysis

Serum-ascitic albumin gradient
>
11 g/L suggestive of cirrhotic rather
than malignant ascites
 John: serum albumin 24, ascitic
albumin 3
• 24 – 3 = 21

Polymorph count >250 suggests
spontaneous bacterial peritonitis
Management of Ascites

What strategies would you use?
Fluid restriction
 Sodium restriction
 Frusemide
 Spironolactone
 Refer for therapeutic large volume
paracentesis

Management of Ascites

What strategies would you use?
Fluid restriction
 Sodium restriction
 Frusemide
 Spironolactone
 Refer for therapeutic large volume
paracentesis

Sodium and Water Restriction


In patients with moderate ascites dietary
restriction of Na+:

Facilitates elimination of ascites

Delays re-accumulation

Oral Na <88mmol/day
Fluid restriction

Serum Na<120 mmol/L
Diuretics
Indications

Mild to moderate ascites

Oedema without ascites

Prevention of ascites recurrence post-LVP
Management of Cirrhotic Ascites
Diuretics
Diuretic type
Distal
Loop
SE’s
Name
Dose
Spironolactone
< 400 mg/d
Anti-androgenic
Hyperkalaemia
Azotaemia
Renal tubular acidosis
Amiloride
< 30 mg/d
Hyperkalaemia
Frusemide
< 160 mg/d
Hyponatraemia
Hypokalaemia
Azotamia
Refractory Ascites in Cirrhosis:
Definition

Inability to mobilise ascites despite sodium
restriction and max tolerable doses of diuretics


Development of diuretic-related complications




400mg/d spironolactone 160mg/d frusemide
Renal impairment
Hepatic encephalopathy
Electrolyte imbalance
Treated with therapeutic large volume paracentesis
John

Comes back to see you one month later

Fever, mild abdominal pain

Chest clear, dipstick urine NAD, no other
source of infection identified

Diagnostic tap (if available)
Polymorphs 750
 Culture pending

Question
What is the diagnosis?
 What should you do?
 How should he be treated?
 Does he need long-term treatment?

Question

What is the diagnosis?



What is the most likely organism?


Refer to hospital
How should he be treated?


Aerobic GN 70% (E coli, enterococcus)
What should you do?


SPONTANEOUS BACTERIAL PERITONITIS
Presence of > 250 neutrophils/ml diagnostic
Treatment 3rd generation cephalosporin for 10 days
Does he need long-term Abs?

Yes: norfloxacin, co-trimoxazole
SBP Recurrence
Recurrence rate
Norfloxacin prophylaxis
Predictors of recurrence are serum bilirubin > 70 mol/L, PT < 45% of
control, ascitic [protein] < 1 gm/dL
John


Finally sees
gastroenterologist
Has gastroscopy
Complications of Portal
Hypertension Oesophageal Varices
35-80%
25-40%
50-80%
 Varices form at rate of 4-5% per year
 Develop when HVPG > 10 mmHg
 Varices increase from small to large in
12% patients per year in first 2 years
Survive
70%
Re-bleed
20-50%
Die
Medical Management of
Portal Hypertension

Objectives

Prevent of development of varices

Prevent and control gastrointestinal bleeding and
rebleeding

Improve survival without impairment to quality of
life
Primary Prevention of Variceal Bleeding
Treatment options
Treated Better
Treated Worse
Beta-blockers
Bleeding
Variceal ligation
Mortality
Sclerotherapy
0.1
0.2
0.5
1
2
Odds ratio (95% CI)
D’Amico et al. Hepatology 1995
5
10
Prevention of Variceal Bleeding
Beta-Blocker Therapy

What are the objectives of treatment?


25% reduction in HR or pulse < 60 bpm
Which beta-blocker and dose

Propanolol 20-40mg

Risk of initial bleed reduced 50%

Usage limited by:


Contraindications (15-20%)
Side-effects
John





Comes to see you because of tiredness
Didn’t like taking his medication –
propanolol and norfloxacin
One week of melaena
P and BP stable
No aspirin, NSAIDs
 Refer
to emergency department
Endoscopy





Bleeding varix
Variceal ligation
IV octreotide or
terlipressin
IV antibiotics
Secondary
prevention with
propanolol
Hepatorenal Syndrome (HRS)

Defined as development of renal failure in
patients with severe liver disease in the
absence of other identifiable renal
pathology

Annual incidence in patients with ascites is
8% or 40% risk over 5 years
Patient Survival After Diagnosis of HRS
1.0
Survival probability
0.8
Type 2
0.6
0.4
P=0.001
0.2
Type 1
0
0
2
Gines et al. Lancet 2003
4
6
8
Time (months)
10
12
John






Neighbour brings John in to see you
Forgetful, muddled sentences, confused
Alert
Hepatic fetor
Hepatic flap
Afebrile
 What’s
the diagnosis??
Hepatic Encephalopathy
Acute or chronic
 Search for precipitants

Infection
 Renal impairment
 Hyponatraemia
 Dehydration
 Constipation
 GI bleed

Hepatic Encephalopathy

Grade 1



Grade 2 and 3




Subjective changes (personality, dressing apraxia)
Point charts (star, join the dots)
Confusion (increased reflexes)
Agitation
Decreased LOC (depressed reflexes)
Grade 4

Comatose
John

How would you treat this?
Neomycin antibiotic
 Protein restriction
 Lactulose 20ml QID
 Lactulose 20ml daily
 Diazepam

John

How would you treat this?
Neomycin antibiotic
 Protein restriction
 Lactulose 20ml QID
 Lactulose 20ml daily
 Diazepam

Malnutrition in Liver Cirrhosis
Poor dietary
intake
Malabsorption
 protein synthesis
 intestinal protein loss
Catabolic state
Insulin resistance
 substrate utilisation
Malnutrition
Fatigue
Infection
Osteoporosis Impaired wound
healing
Clinical failure: malnutrition
High calorie diet
 No protein restriction
 Frequent small meals
 Dietary supplements
 Ensure adequate calcium and vitamin D
 Pro-kinetic agents
 May need to use NG feeding

Key Points
Chronic Liver Disease

John: recognising and diagnosing CLD

Important investigations in CLD
• Albumin, INR, platelets, bilirubin

Causes
• Alcohol, viral hepatitis, NASH, autoimmune liver disease,
haemochromatosis
• Viral serology, iron studies, autoimmune screen


Treat underlying disease early (prevention)
All cirrhotic patients referred for evaluation
Key Points
Complications
HBV vaccination
 Increase surveillance and clinical suspicion

Sodium restriction and spironolactone for
ascites
 Melaena needs urgent assessment
 Propanolol for prevention variceal bleeding
 Lactulose for encephalopathy
 Good nutrition
